EP2233487A1 - Dérivés de cyclohéxane spirocycliques - Google Patents

Dérivés de cyclohéxane spirocycliques Download PDF

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Publication number
EP2233487A1
EP2233487A1 EP20100005484 EP10005484A EP2233487A1 EP 2233487 A1 EP2233487 A1 EP 2233487A1 EP 20100005484 EP20100005484 EP 20100005484 EP 10005484 A EP10005484 A EP 10005484A EP 2233487 A1 EP2233487 A1 EP 2233487A1
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Prior art keywords
dimethylamino
polysubstituted
unsubstituted
alkyl
monosubstituted
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German (de)
English (en)
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EP2233487B1 (fr
Inventor
Claudia Dr. Hinze
Otto Aulenbacher
Bernd Dr. Sundermann
Stefan Dr. Oberbörsch
Elmar Dr. Friderichs
Werner Dr. Englberger
Babette-Yvonne Dr. Kögel
Klaus Dr. Linz
Hans Dr. Schick
Helmut Dr. Sonnenschein
Birgitta Dr. Henkel
Valerie Sarah Dr. Rose
Michael Jonathan Dr. Lipkin
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Gruenenthal GmbH
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Gruenenthal GmbH
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Definitions

  • the invention therefore relates to splrocyclic cyclohexane derivatives of the general forms I, in which R 1 and R 2 are independently H; CHO; C 1-5 alkyl in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C 3-8 -cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; or C 1-3 alkyl bonded aryl, C 3-8 cycloalkyl or heteroaryl, Jewells-mono- or polysubstituted or unsubstitulert stand; or the radicals R 1 and R 2 together are CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 11 CH 2 CH 2 or (CH 2 ) 3-6 , wobel R 11 H; C 1-5 alkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysub
  • the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or dlastereomer the bases and / or salts of physiologically acceptable acids or cations.
  • aryl in the context of this invention means carbocyclic ring systems having at least one aromatic ring, but without heteroatoms In only one of Rings, including phenyls, naphthyls and phenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.
  • the aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical can be unsubstituted or monosubstituted or polysubstituted, the aryl substituents being the same or different and being able to be in any belleblen and possible position of the aryl.
  • Particularly advantageous are phenyl or naphthyl radicals.
  • Mandelic acid fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxoproline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ - Lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid,
  • R 3 is phenyl, benzyl or phenethyl, in each case unsubstituted or monosubstituted or polysubstituted on the ring; means
  • Oral or percutaneously applicable preparation forms can release the spirocyclic cyclohexane derivatives according to the invention with a delay.
  • the spirocyclic cyclohexane derivatives of the invention can also be used in parenteral long-term depot forms such. As implants or implanted pumps are applied. In principle, other active compounds known to the person skilled in the art may be added to the medicaments according to the invention.
  • the medicament contains, in addition to at least one spirocyclic cyclohexane derivative, another active substance, in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane.
  • an opioid preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane.
  • Example 1 has advantages with respect to the cardiovascular compatibility in comparison to the two clinically used opioids fentanyl and sufentanli.
  • Example 25 1,1- (3-Dimethylamino-3-phenylpentamethylene) -6-fluoro-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate, more polar diastereoisomer
  • Example 27 1,1- (3-Dimethylsmino-3-phenylpentamethylene) -9-phenyl-1,3,4,9-tetrahydropyrano [3,4-b] indole citrate
  • Example 28 1,1- (3-Methylamino-3-phenylpentamethylene) -1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate.
  • the batch was diluted with water (30 ml), adjusted to pH 11 with NaOH (5 mol / l) and extracted with 1,2-dichloroethane (3 ⁇ 30 ml). The organic phase was dried with sodium sulfate and concentrated. The brown solid residue was recrystallized from methanol. There was obtained 236 mg of a white solid. 100 mg of this was dissolved in hot ethanol (10 ml) and treated with an equally hot solution of citric acid (62 mg, 0.32 mmol) in ethanol (1 ml). After cooling to about 5 ° C, the approach was allowed to stand for 4 h. The resulting solid was filtered off with suction.
  • Example 32 2-acetyl-1,1- (3-dimethylamino-3-phenylpentamethylen) -7-fluoro-3,4-dihydro-1 H -2,9-diazafluorene citrate, more non-polar Diastereolsomer
  • the batch was diluted with water (20 ml), adjusted to pH 11 with NaOH (5 mol / l) and with 1,2-dichloroethane (3 x 20 ml) extrahlert.
  • the organic phase was dried with sodium sulfate and concentrated.
  • the back end was a contaminated mixture of the two diastereoisomeric 1,1- (3-dimethylamino-3-phenyl-pentamethylene) -3-methyl-3,4-dihydro-1 H -2,9-diazafluorenes which were purified by recrystallization from methanol but could not be separated (660 mg of white solid).
  • Beisplel 34 1,1- (3-dimethylamino-3-phenylpentamethylen) -6-fluoro-3,4-dihydro-1H-2,9-diazafluorene dihydrochloride
  • the dihydrochloride of 1,1- (3-dimethylamino-3-phenylpentamethylen) obtained -6-fluoro-3,4-dihydro-1 H -2,9-diazafluorene (131 mg of white solid, m.p. 228-232 ° C) was a 60:40 mixture of the two diastereoisomers.
  • Example 39 1,1- (3-Dimethylamino-3- (4-fluorophenyl) pentamethylene) -1,3,4,9-tetra-hydro-2-thia-9-azafluorene Methanesulfonate
  • the precipitated methanesulfonate was filtered off with suction, washed with DCM (3 ⁇ 1 ml) and diethyl ether (3 ⁇ 3 ml).
  • the methanesulfonate of one of the two possible diastereol isomers of 1,1- (3-dimethylamino-3- (4-fluorophenyl) penta-methylene) -1,3,4,9-tetrahydro-2-thia-9-azafluorene was obtained in a yield of 550 mg as a white solid (mp 245-250 ° C).
  • Example 44 1,1- (3-Dimethylamino-3-phonylpentamethylene) -6-bromo-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
  • Example 46 (3 S) -1,1- (3-dimethylamino-3-phenylpentamethylen) -3,4-dihydro-3-methoxycarbonyl-1 H -2,9-diazafluorene citrate
  • the batch was diluted with water (20 ml) and adjusted to pH 11 with NaOH (5 mol / l).
  • EA 20 mL
  • a white solid precipitated, which was suctioned off.
  • the solid was washed with water (3 x 5 mL) and dried.
  • This 600 mg was dissolved in hot ethanol (30 ml) and treated with an equally hot solution of citric acid (276 mg, 1.44 mmol) in ethanol (5 ml). After cooling to about 5 ° C, the approach was allowed to stand for 4 h.
  • Example 50 1,1- (3-Dimethylamino-3- (4-fluorophenyl) pentamethylene) -3,4-dihydro-1H-2,9-dithiol fluorene methanesulfonate
  • the percentage displacement of the radioactive ligand from its binding to the human ⁇ -opiate receptor at a concentration of the test substances of 1 .mu.mol / l was determined and expressed as a percentage inhibition (% inhibition) of the specific binding.
  • IC 50 inhibitory concentrations were calculated, which cause a 50% displacement of the radioactive ligand.
  • Ki values were obtained for the test substances.
  • mice were each placed alone in a test cage and the tail base exposed to the focused heat beam of an electric lamp (tail-flick type 50/08 / 1.bc, Labtec, Dr. Hess).
  • the lamp intensity was adjusted so that the time from switching on the lamp to the sudden winceing of the tail (pain latency) in untreated mice was 3 to 5 seconds.
  • the mice were pretested twice within five minutes and the mean value of these measurements was calculated as the preliminary test value.

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